There are important differences in cognitive, immunological and metabolic functions as well as longevity between the sexes. For example, autism is~5-fold more prevalent in boys, and ischemic heart disease (IHD) ~2-fold more common and seen at an earlier age in men, while autoimmune diseases are several times more common in girls and women. Our goal is to elucidate the genetic and physiological mechanisms underlying these important but poorly understood differences. The major reason for the greater longevity of women is their relative protection, across all age groups, from ischemic heart disease (IHD). The traditional idea that estrogen protects women against IHD has recently been called into question. To investigate the potential contribution of X-chromosome gene(s) to women's protection from IHD, we examined IHD risk factors in women with monosomy X, or Turner syndrome (TS). TS is characterized by short stature, premature ovarian failure, cardiovascular anomalies and premature IHD. To control for the ovarian failure in TS, we compared glucose tolerance, lipid metabolism and blood pressure and in lean, young women with TS and age- and body composition-matched women with 46,XX premature ovarian failure (POF). Diabetes mellitus (DM) is a major cardiac risk factor. We have shown that while most girls and women with TS have normal fasting glucose and insulin, the glycemic response to a glucose challenge is dramatically abnormal and consistent with diabetes in about 40%, and is significantly above the POF control group in all women with TS. Interestingly, the glucose intolerance in these young lean women and girls with TS is not explained by insulin resistance, but by a novel insulin secretory defect. The insulin response to an oral or IV glucose challenge is significantly lower than POF or normal controls in all women with TS. It thus appears that the Turner ?metabolic syndrome? is a distinct entity characterized by decreased insulin secretion, reminiscent of mature onset diabetes of the young (MODY) syndromes, caused by haploinsufficiency for autosomal genes involved in pancreatic development-- suggesting that haploinsufficiency for unknown X-chromosome gene(s) impairs beta cell function and predisposes to DM in TS. We have also found LDL cholesterol and triglycerides are all significantly increased in TS compared to age- and BMI-matched women with POF. Moreover, NMR spectroscopy revealed a concentration of smaller, denser HDL and LDL lipid particles in women with TS. These data show a distinctly atherogenic lipid profile in otherwise healthy, non-obese young women with TS. There are at least two major mechanisms whereby a 2nd X chromosome could contribute to lipid homeostasis. First, X-chromosome genes involved in lipid metabolism or clearance may escape inactivation and thus normally be active in two copies in 46.XX women, but only one copy in men. Alternatively, parental imprinting of X-chromosome genes involved in BP may have favorable effects in women. For example, a gene that exerts a moderating effect could be imprinted, or silenced on the maternal X (Xmat) but active from the paternal X allele. Since men only receive the Xmat, they would not experience the moderating effects on BP, but normal women with random X inactivation would express the Xpat allele in about 50% of their cells. To test this hypothesis, we compared lipid profiles in healthy young women matched for age, body mass and the presence of ovarian failure (eliminating the sex steroid variable). The experimental variable was the X-chromosome: study groups included women with Turner syndrome and a paternal X (45,XP), women with TS and a maternal X (45,XM) and karyotypically normal women (46,XPXM). LDL-cholesterol levels were highest in TS,XM women, intermediate in 46,XX women and lowest in TS,XP women, with differences between each group being highly statistically significant. Women with monosomy for XM exhibit a relatively atherogenic lipid profile compared to 46,XMXP women, while women monosomic for XP have a significantly better lipid profile. These data suggest that genomic imprinting of X-linked gene(s) may contribute to differences in lipid metabolism and longevity between normal men (46,XMY) and women. Ovarian failure occurring in a young woman is likely to have major psychological impact, but the specific consequences of this diagnosis in terms of self image and psychosocial function have not been systematically investigated. To evaluate psychosocial function in two different groups of young women with clearly established diagnoses of ovarian failure compared to women with normal ovarian function, we administered standardized measures of social functioning and mood to women with Turner syndrome (TS, n = 100), women with karyotypically-normal premature ovarian failure (POF, n = 100) and control women with normal ovarian function (n = 35). TS and POF groups had nearly identical scores on all four scales of psychosocial function. Both groups reported higher levels of shyness (p < 0.0004), social anxiety (p < 0.0001), and depression (p < 0.0001) and significantly lower self-esteem (p < 0.0004) compared with normal controls. Thus, young women differing in many respects but sharing a common diagnosis of premature ovarian failure report virtually identical traits of increased shyness, social anxiety and depression and decreased self-esteem compared to women with normal ovarian function. These observations suggest that ovarian failure per se causes significant psychosocial distress in many young women, and that attention to psychological health and social functioning should be an important part of their care.